Refining frailty in relapsed or refractory multiple myeloma: adding the patient voice
Authors: Kelly L Schoenbeck, Tanya M Wildes
Journal: The Lancet Healthy Longevity (2022)

Multiple myeloma is an incurable haematological malignancy with a rapidly evolving treatment landscape. Despite novel therapies, ageing-associated vulnerabilities can complicate the treatment of older adults with this condition.1Costa LJ Brill IK Omel J Godby K Kumar SK Brown EE Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States.Blood Advances. 2017; 1: 282-287Crossref PubMed Scopus (176) Google Scholar The International Myeloma Working Group (IMWG) frailty score predicts treatment-related toxicity and mortality for older adults with newly diagnosed multiple myeloma. By use of objective data (age, activities of daily living, instrumental activities of daily living, and Charlson Comorbidity Index), patients are categorised as fit, intermediate-fit, or frail. Frail patients are at higher risk of grade 3–4 toxicities, treatment discontinuation, and decreased overall survival.2Palumbo A Bringhen S Mateos MV et al.Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report.Blood. 2015; 125: 2068-2074Crossref PubMed Scopus (457) Google ScholarThe IMWG frailty score predicts how older adults with newly diagnosed multiple myeloma might fare on treatment, but does not incorporate experiences directly from patients. Patient-reported outcomes provide insight into medical conditions from the perspective of patients without interpretation from others.3US Food and Drug AdministrationGuidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims. US Department of Health and Human Services Food and Drug Administration.https://www.fda.gov/media/77832/downloadDate accessed: July 31, 2022Google Scholar Patient-reported outcome measures can quantify symptoms and health-related quality of life to help guide treatment discussions between patients and clinicians. Patient-reported outcome measures are important for patients with relapsed or refractory multiple myeloma, because as their disease becomes more challenging to treat, balancing survival with quality of life becomes a priority.4LeBlanc MR Hirschey R Leak Bryant A LeBlanc TW Smith SK How are patient-reported outcomes and symptoms being measured in adults with relapsed/refractory multiple myeloma? A systematic review.Qual Life Res. 2020; 29: 1419-1431Crossref PubMed Scopus (15) Google ScholarAlthough the IMWG frailty score and patient-reported outcomes are both important for evaluating older adults with multiple myeloma, they have not been previously studied in conjunction. The accompanying Article by Fabio Efficace and colleagues5Efficace F Gaidano G Petrucci M et al.Association of IMWG frailty score with health-related quality of life profile of patients with relapsed refractory multiple myeloma in Italy and the UK: a GIMEMA, multicentre, cross-sectional study.Lancet Healthy Longev. 2022; 3: e628-e635Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar presents a novel way to characterise patients with relapsed or refractory multiple myeloma by evaluating the association between patient-reported outcomes and the IMWG frailty index. The authors present the baseline results of 415 patients from their ongoing, multisite trial, using established patient-reported outcome measures. There were no substantial differences in frailty based on previous stem cell transplantation, number of treatments, or grade 3 toxicities or higher. Patient-reported outcomes identified distinct patient profiles across frailty scores, with frail patients having worse functioning and higher symptom burden than fit patients. The largest clinically meaningful adjusted differences between fit patients and frail patients (according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core30) were observed for physical functioning (Δ=–19·0 [95% CI –25·6 to –12·5; p<0·0001), fatigue (Δ=16·7 [9·7 to 23·7]; p<0·0001), insomnia (Δ=13·4 [4·1 to 22·6]; p=0·0047), and dyspnoea (Δ=12·5 [4·6 to 20·4]; p=0·0021). The authors conclude the unique profiles support utility of the IMWG frailty score in patients with relapsed or refractory multiple myeloma.Efficace and colleagues demonstrate that patient-reported outcomes can be used to identify distinct symptom profiles and functional limitations among the IMWG frailty groups, providing a more granular understanding of the patient experience. Patient-reported outcomes can also predict clinical outcomes, including health-care utilisation6Mian H Sutradhar R Pond GR et al.Patient-reported outcome measures are associated with health care utilization in patients with transplant ineligible multiple myeloma: a population-based study.Blood Cancer Journal. 2022; 12: 17Crossref PubMed Scopus (2) Google Scholar and prognostication, with a decline of physical function by patient-reported outcomes being associated with increased risk of death.7Efficace F Collins GS Cottone F et al.Patient-reported outcomes as independent prognostic factors for survival in oncology: systematic review and meta-analysis.Value Health. 2021; 24: 250-267Summary Full Text Full Text PDF PubMed Scopus (28) Google Scholar In this study, patient-reported physical function was significantly different among the frailty groups, with the largest difference between frail and fit patients with relapsed or refractory multiple myeloma. Although it might appear intuitive that frail patients would have decreased physical function by patient-reported outcomes, some patients might be classified as frail with the IMWG score simply by virtue of an age of 80 years and older, thereby combining patients who are independent octogenarians with younger patients who have functional dependence and substantial comorbidities. Clinically important variability among frail patients was exemplified in a trial in which patients categorised as frail by age alone had better survival than those considered frail for other factors.8Stege CAM Nasserinejad K van der Spek E et al.Ixazomib, daratumumab, and low-dose dexamethasone in frail patients with newly diagnosed multiple myeloma: the Hovon 143 Study.JCO. 2021; 39: 2758-2767Crossref PubMed Scopus (9) Google Scholar We suggest that future studies should further refine the categorisations of frailty used in multiple myeloma and examine patient-reported outcomes in older patients with relapsed or refractory multiple myeloma stratified by whether they are considered frail by age alone or by other ageing-associated vulnerabilities.Although the study is innovative for evaluating the relationship between the IMWG frailty score and patient-reported outcomes, questions remain. Patients with relapsed or refractory multiple myeloma are very heterogeneous regarding their current and previous treatment, the presence of toxicities of previous therapy, and symptoms caused by disease activity. This heterogeneity makes the timing of the baseline assessments essential for putting the results of patients with relapsed or refractory multiple myeloma into context. Although most patients were on treatment at time of study entry, if the patient-reported outcome measures were performed at time of new treatment initiation, if the treatment was long-standing, or if patients were off therapy, remains unclear. Were patients experiencing symptomatic relapse or biochemical progression? Similarly, patients' response to therapy at time of assessment is crucial because patient-reported outcomes of patients with relapsed or refractory multiple myeloma are associated with disease state: patient-reported outcomes improve in patients who respond to therapy and worsen in those with disease progression.9Oriol A Ibarra G Abella E et al.Impact of response to treatment in health-related quality of life patient-reported outcomes in elderly patients with relapsed multiple myeloma.Leuk Lymphoma. 2021; 62: 125-135Crossref PubMed Scopus (1) Google Scholar We anticipate that the results of the authors' ongoing prospective cohort study will provide a deeper understanding of the association between patient-reported outcomes and IMWG frailty scores.In summary, we commend Efficace and colleagues for their novel evaluation of patient-reported outcomes with the IMWG frailty score, laying important groundwork for future studies on how to approach assessments of older adults with relapsed or refractory multiple myeloma. Multiple myeloma is an incurable haematological malignancy with a rapidly evolving treatment landscape. Despite novel therapies, ageing-associated vulnerabilities can complicate the treatment of older adults with this condition.1Costa LJ Brill IK Omel J Godby K Kumar SK Brown EE Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States.Blood Advances. 2017; 1: 282-287Crossref PubMed Scopus (176) Google Scholar The International Myeloma Working Group (IMWG) frailty score predicts treatment-related toxicity and mortality for older adults with newly diagnosed multiple myeloma. By use of objective data (age, activities of daily living, instrumental activities of daily living, and Charlson Comorbidity Index), patients are categorised as fit, intermediate-fit, or frail. Frail patients are at higher risk of grade 3–4 toxicities, treatment discontinuation, and decreased overall survival.2Palumbo A Bringhen S Mateos MV et al.Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report.Blood. 2015; 125: 2068-2074Crossref PubMed Scopus (457) Google Scholar The IMWG frailty score predicts how older adults with newly diagnosed multiple myeloma might fare on treatment, but does not incorporate experiences directly from patients. Patient-reported outcomes provide insight into medical conditions from the perspective of patients without interpretation from others.3US Food and Drug AdministrationGuidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims. US Department of Health and Human Services Food and Drug Administration.https://www.fda.gov/media/77832/downloadDate accessed: July 31, 2022Google Scholar Patient-reported outcome measures can quantify symptoms and health-related quality of life to help guide treatment discussions between patients and clinicians. Patient-reported outcome measures are important for patients with relapsed or refractory multiple myeloma, because as their disease becomes more challenging to treat, balancing survival with quality of life becomes a priority.4LeBlanc MR Hirschey R Leak Bryant A LeBlanc TW Smith SK How are patient-reported outcomes and symptoms being measured in adults with relapsed/refractory multiple myeloma? A systematic review.Qual Life Res. 2020; 29: 1419-1431Crossref PubMed Scopus (15) Google Scholar Although the IMWG frailty score and patient-reported outcomes are both important for evaluating older adults with multiple myeloma, they have not been previously studied in conjunction. The accompanying Article by Fabio Efficace and colleagues5Efficace F Gaidano G Petrucci M et al.Association of IMWG frailty score with health-related quality of life profile of patients with relapsed refractory multiple myeloma in Italy and the UK: a GIMEMA, multicentre, cross-sectional study.Lancet Healthy Longev. 2022; 3: e628-e635Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar presents a novel way to characterise patients with relapsed or refractory multiple myeloma by evaluating the association between patient-reported outcomes and the IMWG frailty index. The authors present the baseline results of 415 patients from their ongoing, multisite trial, using established patient-reported outcome measures. There were no substantial differences in frailty based on previous stem cell transplantation, number of treatments, or grade 3 toxicities or higher. Patient-reported outcomes identified distinct patient profiles across frailty scores, with frail patients having worse functioning and higher symptom burden than fit patients. The largest clinically meaningful adjusted differences between fit patients and frail patients (according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core30) were observed for physical functioning (Δ=–19·0 [95% CI –25·6 to –12·5; p<0·0001), fatigue (Δ=16·7 [9·7 to 23·7]; p<0·0001), insomnia (Δ=13·4 [4·1 to 22·6]; p=0·0047), and dyspnoea (Δ=12·5 [4·6 to 20·4]; p=0·0021). The authors conclude the unique profiles support utility of the IMWG frailty score in patients with relapsed or refractory multiple myeloma. Efficace and colleagues demonstrate that patient-reported outcomes can be used to identify distinct symptom profiles and functional limitations among the IMWG frailty groups, providing a more granular understanding of the patient experience. Patient-reported outcomes can also predict clinical outcomes, including health-care utilisation6Mian H Sutradhar R Pond GR et al.Patient-reported outcome measures are associated with health care utilization in patients with transplant ineligible multiple myeloma: a population-based study.Blood Cancer Journal. 2022; 12: 17Crossref PubMed Scopus (2) Google Scholar and prognostication, with a decline of physical function by patient-reported outcomes being associated with increased risk of death.7Efficace F Collins GS Cottone F et al.Patient-reported outcomes as independent prognostic factors for survival in oncology: systematic review and meta-analysis.Value Health. 2021; 24: 250-267Summary Full Text Full Text PDF PubMed Scopus (28) Google Scholar In this study, patient-reported physical function was significantly different among the frailty groups, with the largest difference between frail and fit patients with relapsed or refractory multiple myeloma. Although it might appear intuitive that frail patients would have decreased physical function by patient-reported outcomes, some patients might be classified as frail with the IMWG score simply by virtue of an age of 80 years and older, thereby combining patients who are independent octogenarians with younger patients who have functional dependence and substantial comorbidities. Clinically important variability among frail patients was exemplified in a trial in which patients categorised as frail by age alone had better survival than those considered frail for other factors.8Stege CAM Nasserinejad K van der Spek E et al.Ixazomib, daratumumab, and low-dose dexamethasone in frail patients with newly diagnosed multiple myeloma: the Hovon 143 Study.JCO. 2021; 39: 2758-2767Crossref PubMed Scopus (9) Google Scholar We suggest that future studies should further refine the categorisations of frailty used in multiple myeloma and examine patient-reported outcomes in older patients with relapsed or refractory multiple myeloma stratified by whether they are considered frail by age alone or by other ageing-associated vulnerabilities. Although the study is innovative for evaluating the relationship between the IMWG frailty score and patient-reported outcomes, questions remain. Patients with relapsed or refractory multiple myeloma are very heterogeneous regarding their current and previous treatment, the presence of toxicities of previous therapy, and symptoms caused by disease activity. This heterogeneity makes the timing of the baseline assessments essential for putting the results of patients with relapsed or refractory multiple myeloma into context. Although most patients were on treatment at time of study entry, if the patient-reported outcome measures were performed at time of new treatment initiation, if the treatment was long-standing, or if patients were off therapy, remains unclear. Were patients experiencing symptomatic relapse or biochemical progression? Similarly, patients' response to therapy at time of assessment is crucial because patient-reported outcomes of patients with relapsed or refractory multiple myeloma are associated with disease state: patient-reported outcomes improve in patients who respond to therapy and worsen in those with disease progression.9Oriol A Ibarra G Abella E et al.Impact of response to treatment in health-related quality of life patient-reported outcomes in elderly patients with relapsed multiple myeloma.Leuk Lymphoma. 2021; 62: 125-135Crossref PubMed Scopus (1) Google Scholar We anticipate that the results of the authors' ongoing prospective cohort study will provide a deeper understanding of the association between patient-reported outcomes and IMWG frailty scores. In summary, we commend Efficace and colleagues for their novel evaluation of patient-reported outcomes with the IMWG frailty score, laying important groundwork for future studies on how to approach assessments of older adults with relapsed or refractory multiple myeloma. KLS reports funding from the American Society of Hematology. TMW reports funding from Janssen and Sanofi. Association of IMWG frailty score with health-related quality of life profile of patients with relapsed refractory multiple myeloma in Italy and the UK: a GIMEMA, multicentre, cross-sectional studyOur findings show the clinical utility of the IMWG frailty score in the setting of relapsed or refractory multiple myeloma, in helping to distinguish between groups of patients with distinct health-related quality of life profiles. Further research is needed to examine the value of patient-reported outcome data in improving assessment of frailty in the setting of relapsed or refractory multiple myeloma. 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